This invention relates generally to novel guanidine mimics which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
WO 96/28427 describes benzamidine anticoagulants of the formula: 
wherein Z1 and Z2 are O, N(R), S or OCH2 and the central ring may be phenyl or a variety of heterocycles. The presently claimed compounds do not contain the Z1 linker or the substitution pattern of the above compounds.
WO 95/13155 and PCT International Application U.S. 96/07692 describe isoxazoline and isoxazole fibrinogen receptor antagonists of the formula: 
wherein R1 may be a basic group, Uxe2x80x94V may be a six-membered aromatic ring, Wxe2x80x94X may be a variety of linear or cyclic groups, and Y is an oxy group. Thus, these compounds all contain an acid functionality (i.e., Wxe2x80x94Xxe2x80x94C(xe2x95x90O)xe2x80x94Y). In contrast, the presently claimed compounds do not contain such an acid functionality.
EP 0,513,387 depicts active oxygen inhibitors which are oxazoles or thiazoles of the formula: 
wherein X is O or S, R2 is preferably hydrogen, and both R1 and R3 are substituted cyclic groups, with at least one being phenyl. The presently claimed invention does not relate to these types of oxazoles or thiazoles.
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula: 
wherein R1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.
In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula: 
wherein the heterocycle may be aromatic and groups Axe2x80x94Bxe2x80x94Cxe2x80x94 and Fxe2x80x94Exe2x80x94Dxe2x80x94 are attached to the ring system. Axe2x80x94Bxe2x80x94Cxe2x80x94 can be a wide variety of substituents including a basic group attached to an aromatic ring. The Fxe2x80x94Exe2x80x94Dxe2x80x94 group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT1 agonists which are indole substituted five-membered heteroaromatic compounds of the formula: 
wherein R1 may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Baker et al, in WO 94/02477, discuss 5-HT1 agonists which are imidazoles, triazoles, or tetrazoles of the formula: 
wherein R1 represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. But, Baker et al do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Tidwell et al, in J. Med. Chem. 1978, 21(7), 613-623, describe a series of diarylamidine derivatives including 3,5-bis(4-amidinophenyl)isoxazole. This series of compounds was tested against thrombin, trypsin, and pancreatic kallikrein. The presently claimed invention does not include these types of compounds.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa Can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
Accordingly, one object of the present invention is to provide novel guanidine mimics which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein D, E, and M are defined below, are effective factor Xa inhibitors.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring D is selected from xe2x80x94CH2Nxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2Nxe2x95x90CHxe2x80x94, a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S;
ring D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
ring E contains 0-2 N atom and is substituted by 0-1 R
R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl) , N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2;
M is selected from the group: 
J is O or S;
Ja is NH or NR1a;
Z is selected from a bond, C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O) (CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, Nxe2x80x94S, NCH2N, NCH2O, or NCH2S bond with ring M or group A;
R1a and R1b are independently absent or selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, R1a and R1b, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or saturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
alternatively, when Z is C(O)NH and R1a is attached to a ring carbon adjacent to Z, then R1a is a C(O) which replaces the amide hydrogen of Z to form a cyclic imide;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, CH(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is selected from:
H, Y, and Xxe2x80x94Y;
X is selected from C1-4 alkylene, xe2x80x94CR2(CR2R2b)(CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR1xe2x80x3)xe2x80x94, xe2x80x94CR2(NR1xe2x80x3R2)xe2x80x94, xe2x80x94CR2(OR2)xe2x80x94, xe2x80x94CR2(SR2)xe2x80x94, xe2x80x94C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O), xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR2R2axe2x80x94, CR2R2aS(O)pxe2x80x94, xe2x80x94S(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2xe2x80x94, xe2x80x94NR2S(O)2CR2R2axe2x80x94, xe2x80x94CR2R2aS(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2NR2xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)Oxe2x80x94, xe2x80x94OC(O)NR2xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and OCR2R2axe2x80x94;
Y is selected from:
(CH2)rNR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N, Oxe2x80x94N, or Sxe2x80x94N bond,
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, CH(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
provided that if B is H, then R4 is other than tetrazole, C(O)-alkoxy, and C(O)NR2R2a;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rNR2R2b, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, C(O)NHSO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(xe2x95x90NR3)NR3R3a, NH3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl
n is selected from 0, 1, 2, and 3;
m is selected from 0, 1, and 2;
p is selected from 0, 1, and 2;
r is selected from 0, 1, 2, and 3;
s is selected from 0, 1, and 2; and,
t is selected from 0 and 1.
[2] In a preferred embodiment, the present invention provides novel compounds, wherein:
Dxe2x80x94E is selected from the group:
1-aminoisoquinolin-7-yl; 1,3-diaminoisoquinolin-7-yl; 1,4-diaminoisoquinolin-7-yl; 1,5-diaminoisoquinolin-7-yl; 1,6-diaminoisoquinolin-7-yl; 1-amino-3-hydroxy-isoquinolin-7-yl; 1-amino-4-hydroxy-isoquinolin-7-yl; 1-amino-5-hydroxy-isoquinolin-7-yl; 1-amino-6-hydroxy-isoquinolin-7-yl; 1-amino-3-methoxy-isoquinolin-7-yl; 1-amino-4-methoxy-isoquinolin-7-yl; 1-amino-5-methoxy-isoquinolin-7-yl; 1-amino-6-methoxy-isoquinolin-7-yl; 1-hydroxy-isoquinolin-7-yl; 4-aminoquinazol-6-yl; 2,4-diaminoquinazol-6-yl; 4,7-diaminoquinazol-6-yl 4,8-diaminoquinazol-6-yl; 1-aminophthalaz-7-yl; 1,4-diaminophthalaz-7-yl; 1,5-diaminophthalaz-7-yl; 1,6-diaminophthalaz-7-yl; 4-aminopterid-6-yl; 2,4-aminopterid-6-yl; 4,6-diaminopterid-6-yl; 8-amino-1,7-naphthyrid-2-yl; 6,8-diamino-1,7-naphthyrid-2-yl; 5,8-diamino-1,7-naphthyrid-2-yl; 4,8-diamino-1,7-naphthyrid-2-yl; 3,8-diamino-1,7-naphthyrid-2-yl; 5-amino-2,6-naphthyrid-3-yl; 5,7-diamino-2,6-naphthyrid-3-yl; 5,8-diamino-2,6-naphthyrid-3-yl; 1,5-diamino-2,6-naphthyrid-3-yl; 5-amino-1,6-naphthyrid-3-yl; 5,7-diamino-1,6-naphthyrid-3-y; 5,8-diamino-1,6-naphthyrid-3-yl; 2,5-diamino-1,6-naphthyrid-3-yl; 3-aminoindazol-5-yl; 3-hydroxyindazol-5-yl; 3-aminobenzisoxazol-5-yl; 3-hydroxybenzisoxazol-5-yl; 3-aminobenzisothiazol-5-yl; 3-hydroxybenzisothiazol-5-yl; 1-amino-3,4-dihydroisoquinolin-7-yl; and, 1-aminoisoindol-6-yl;
M is selected from the group: 
Z is selected from (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, and (CH2)rSO2NR3(CH2)r; and,
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
Y may also be selected from the following bicyclic heteroaryl ring systems: 
K is selected from O, S, NH, and N.
[3] In a more preferred embodiment, the present invention provides novel compounds, wherein;
Dxe2x80x94E is selected from the group:
1-aminoisoquinolin-7-yl; 1,3-diaminoisoquinolin-7-yl; 1,4-diaminoisoquinolin-7-yl; 1,5-diaminoisoquinolin-7-yl; 1,6-diaminoisoquinolin-7-yl; 1-hydroxy-isoquinolin-7-yl; 4-aminoquinazol-6-yl; 2,4-diaminoquinazol-6-yl; 4,7-diaminoquinazol-6-yl; 4,8-diaminoquinazol-6-yl; 1-aminophthalaz-7-yl; 1,4-diaminophthalaz-7-yl; 1,5-diaminophthalaz-7-yl; 1,6-diaminophthalaz-7-yl; 4-aminopterid-6-yl; 8-amino-1,7-naphthyrid-2-yl; 5-amino-1,6-naphthyrid-3-y; 5-amino-2,6-naphthyrid-3-yl; 3-aminobenzisoxazol-5-yl; 3-aminobenzisothiazol-5-yl; 1-amino-3,4-dihydroisoquinolin-7-yl; and, 1-aminoisoindol-6-yl;
M is selected from the group: 
Z is selected from (CH2)rC(O)(CH2)r and (CH2)rC(O)NR3(CH2)r; and,
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole.
[4] In an even more preferred embodiment, the present invention provides novel compounds, wherein;
Dxe2x80x94E is selected from the group:
1-aminoisoquinolin-7-yl; 1,3-diaminoisoquinolin-7-yl; 1,4-diaminoisoquinolin-7-yl; 1,5-diaminoisoquinolin-7-yl; 1,6-diaminoisoquinolin-7-yl; 1-aminophthalaz-7-yl; 1,4-diaminophthalaz-7-yl; 1,5-diaminophthalaz-7-yl; 1,6-diaminophthalaz-7-yl; 4-aminopterid-6-yl; 8-amino-1,7-naphthyrid-2-yl; 5-amino-1,6-naphthyrid-3-y; 5-amino-2,6-naphthyrid-3-yl; 3-aminobenzisoxazol-5-yl; 1-amino-3,4-dihydroisoquinolin-7-yl; and, 1-aminoisoindol-6-yl;
M is selected from the group: 
A is selected from:
C5-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R4b;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, C(O)R2c, CH2C(O)R2c, C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, CH(xe2x95x90NS(O)2R5)NR2R2a, SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, S(O)2R5, and CF3 
provided that if B is H, then R4 is other than tetrazole, C(O)-alkoxy, and C(O)NR2R2a;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, NR2R2b, CH2NR2R2b, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, S(O)2R5, and CF3; and,
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, C1-4 alkyl, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, C(O)NR3R3a, CH(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)2CF3, S(O)2xe2x80x94C1-4 alkyl, S(O)2-phenyl, and CF3.
[5] In a further preferred embodiment, the present invention provides novel compounds wherein:
Dxe2x80x94E is selected from the group:
1-aminoisoquinolin-7-yl; 1,3-diaminoisoquinolin-7-yl; 1,4-diaminoisoquinolin-7-yl; 1,5-diaminoisoquinolin-7-yl; 1,6-diaminoisoquinolin-7-yl; 8-amino-1,7-naphthyrid-2-yl; 5-amino-1,6-naphthyrid-3-y; 5-amino-2,6-naphthyrid-3-yl; 3-aminobenzisoxazol-5-yl; 1-amino-3,4-dihydroisoquinolin-7-yl; and, 1-aminoisoindol-6-yl.
[6] In an even further preferred embodiment, the present invention provides a novel compound selected from:
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(4xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(Isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
3-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]-5-methylisoxazoline;
3-(Isoquinol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]-5-methylisoxazoline;
3-(Isoquinol-7xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]-5-methylisoxazoline;
3-(2xe2x80x2-Aminobenzimidazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline;
3-(3xe2x80x2-Aminoindazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline;
3-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-5-methylisoxazoline
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
3-(1-Amino-isoquinol-7-yl)-4-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole;
3-(4-amino-isoquinol-7-yl)-4-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole;
3-(isoquinol-7-yl)-4-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole;
1-(Quinol-2-ylmethyl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(Quinol-2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminoindazol-5xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3-Aminoindazole-5-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-(phenyl)pyrid-2-ylaminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-methyl-5-[isoquinol-7-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-isopropyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(2xe2x80x2,4xe2x80x2-Diaminoquinazol-6xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(4xe2x80x2-Aminoquinazol-6xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-methyl-5-[4-(N-pyrrolidinylcarbonyl)phenylaminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminopthalazin-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
3-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[[5-[(2xe2x80x2-aminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]-5-(methylsulfonylaminomethyl)isoxazoline;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2-fluoro-4-morpholinophenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-(2xe2x80x2-isopropylimidazol-1xe2x80x2-yl)phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-(2xe2x80x2-ethylimidazol-1xe2x80x2-yl)phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-[(2xe2x80x2-dimethylaminomethyl)imidazol-1xe2x80x2-yl]phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-[(2xe2x80x2-methoxymethyl)imidazol-1xe2x80x2-yl]phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-[(2xe2x80x2-dimethylaminomethyl)imidazol-1xe2x80x2-yl]-2-fluorophenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[(2-methoxy-4-(2xe2x80x2-methylimidazol-1xe2x80x2-yl)phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-(2xe2x80x2-isopropylimidazol-1xe2x80x2-yl)-2-fluorophenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[[4-(2xe2x80x2-ethylimidazol-1xe2x80x2-yl)-2-fluorophenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-(2xe2x80x2-ethylimidazol-1xe2x80x2-yl)-2-fluorophenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-[(2xe2x80x2-methoxymethyl)imidazol-1xe2x80x2-yl]phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-[(2xe2x80x2-dimethylaminomethyl)imidazol-1xe2x80x2-yl]phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-[(2xe2x80x2-methyl)benzimidazol-1xe2x80x2-yl]phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-ethylimidazol-1xe2x80x2-ylphenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-(2xe2x80x2-ethylimidazol-1xe2x80x2-yl)-2,5-difluorophenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2-fluoro-4-morpholinophenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-isopropylimidazol-1xe2x80x2-ylphenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-(2xe2x80x2-methylimidazol-1xe2x80x2-yl)-2-fluorophenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-aminosulfonyl-3-amino-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-aminosulfonyl-3-nitro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[4-(2xe2x80x2-methylimidazol-1xe2x80x2-yl)phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[2-dimethyl-4-(N-pyrrolidinocarbonyl)phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[2-pyrrolidino-4-(N-pyrrolidinocarbonyl)phenyl]-aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[5-[(2xe2x80x2-methylsulfonyl)phenyl]pyrimid-2-yl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[(2xe2x80x2-methylsulfonyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[[5-[(2xe2x80x2-aminosulfonyl)phenyl]pyrid-2-yl]aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[[(2xe2x80x2-methylsulfonyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]aminocarbonyl]tetrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[[4-(2xe2x80x2-methylimidazol-1xe2x80x2-yl)phenyl]aminocarbonyl]tetrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]tetrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]tetrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2-(N-pyrrolidino)-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]tetrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-5-[[(2xe2x80x2-aminosulfonyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl]aminocarbonyl]tetrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-5-[[(2xe2x80x2-methylsulfonyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]tetrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2aminosulfonylphenyl)pyrimidin-2-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[4-(2xe2x80x2-methylimidazol-1xe2x80x2-yl)phenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[4-(2xe2x80x2-methylimidazol-1xe2x80x2-yl)-2-fluorophenyl)aminocarbonyl]pyrazoloe;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[4-(1xe2x80x2-methylimidazol-2xe2x80x2-yl)-2-fluorophenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[4-(2xe2x80x2-aminoimidazol-1xe2x80x2-yi)phenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-dimethylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
Ethyl 1-(3xe2x80x2-aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylic acid;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxamide;
Ethyl 1-(3xe2x80x2-aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylic acid;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-(hydroxymethyl)-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-[dimethylaminomethyl]-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
Ethyl 1-(3xe2x80x2-aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylic acid;
1-(1xe2x80x2,2xe2x80x2,3xe2x80x2,4xe2x80x2-Tetrahydroisoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-[(2xe2x80x2-methylaminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]-5-methylpyrazole;
1-(4xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)-phenyl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(5-(2xe2x80x2-methylsulfonylphenyl)pyrid-2-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminosulfonyl-3-chloro-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminosulfonyl-3-methyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Amino-isoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylaminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carbonylamino]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-methylaminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-propyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-propyl-5-[(2xe2x80x2-methylaminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-propyl-5-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-ethyl-5-[4-(N-pyrrolidinocarbonyl-1-yl)phenylaminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[4-(imidazol-1xe2x80x2-yl)phenylaminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[3-fluoro-4-(2-methylimidazol-1xe2x80x2-yl)phenylaminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[4-(2-methylimidazol-1xe2x80x2-yl)phenylaminocarbonyl]pyrazole;
1-(1xe2x80x2-Aminoisoquinol-7xe2x80x2-yl)-3-trifluoromethyl-5-[2-fluoro-4-(2-methylimidazol-1xe2x80x2-yl)phenylaminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-methyl-5-[(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl-aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(5-(2xe2x80x2-aminosulfonylphenyl)pyrid-2-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(5-(2xe2x80x2-methylsulfonylphenyl)pyrimid-2-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-methyl-5-[(4-(pyrid-3xe2x80x2-yl)phenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(4-(pyrid-3xe2x80x2-yl-3-fluorophenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminoindazol-51-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminoindazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminoindazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[2-fluoro-4-(N-pyrrolidinocarbonyl)phenylaminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminoindazol-5xe2x80x2-yl)-3-methyl-5-[(4-(pyrid-3xe2x80x2-yl)phenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminoindazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(4-(pyrid-3xe2x80x2-yl-3-fluorophenyl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminomethylnaphth-2xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-hydroxymethyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-51-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-methylaminomethyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-bromomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-pyridiniummethyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-aminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-N-pyrrolidinylmethyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-imidazol-1l-yl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[((2xe2x80x2-(4xe2x80x3-t-butoxycarbonyl)piperazin-1xe2x80x3-ylmethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[((2xe2x80x2-(N,N-dimethylamino)pyridiniummethyl)-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-piperazin-1xe2x80x3-ylmethyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-N-methylmorpholiniummethyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-morpholinomethyl-[1,1xe2x80x2]-biphen-4-yl) amiocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(3-fluoro-2xe2x80x2-(N-methyl-N-methoxyamino)-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]triazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-aminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]triazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-trifluoromethyl-5-[(2xe2x80x2-methylaminosulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-5-[(2xe2x80x2-dimethylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]tetrazole;
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[(2xe2x80x2-dimethylaminomethyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]pyrazole; and,
1-(3xe2x80x2-Aminobenzisoxazol-5xe2x80x2-yl)-3-ethyl-5-[4xe2x80x2-(2xe2x80x3-dimethylaminomethylimidazol-1xe2x80x3-yl)-2xe2x80x2-fluorophenyl)aminocarbonyl]pyrazole;
or a pharmaceutically acceptable salt thereof.
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-6 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl(tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfdmic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
One general synthesis of compounds of Formula I where ring M is N-linked is shown in Scheme la. Q, Bxe2x80x2 and Rf are protected functional groups that can be converted to R, B and R1a respectively. Dxe2x80x94E can also be called PI, the sidechain that fits into the SI pocket of fXa. The compounds can also be obtained by changing the sequences of the reaction steps as described in Scheme 1a. For N-linked M ring, the appropriate heterocyclic aniline is treated under conditions described in xe2x80x9cThe Chemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, E. C. Ed., John Wiley and Sonsxe2x80x9d or as described later in the synthesis section to give N-linked ring M. Further modifications and deprotections give N-linked ring M with R, Zxe2x80x94Axe2x80x94B and R1a substitutents. 
In Scheme 1b is shown how to obtain compounds wherein ring M is C-linked and is either five- or six-membered. The aniline from Scheme la is diazotized with nitrous acid and treated with NaBr to give the heterocyclic bromide. Treatment with n-BuLi followed by DMF gives an aldehyde which can be converted to ring M as described in xe2x80x9cThe Chemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, E. C. Ed., John Wiley and Sonsxe2x80x9d or as will be described. Other precursor functional groups like acid, cyanide, methylketone, etc. can also be used to form the ring M. Further modifications and deprotections can yield five-membered ring M substituted with R, Zxe2x80x94Axe2x80x94B and R1a. The corresponding C-linked six-membered ring M can be obtained by converting the above bromide with n-butyl lithium and triisopropyl borate to give the heterocyclic boronic acid. Suzuki coupling with the appropriate heterocyclic bromide, followed by modifications and deprotections gives the C-linked six-membered ring M with R, Zxe2x80x94Axe2x80x94B and R1a substituents. 
Scheme 2a shows the synthesis of 2-aminoisoquinoline P1 in which the groups R1a and Zxe2x80x94Axe2x80x94B are attached to the pyrazole C-3 and C-5 respectively. Synthesis begins with 7-aminoisoquinoline (J. Chem. Soc. 1951, 2851). Diazotization and reduction with stannous chloride converts the aryl amine to a hydrazine (J. Org. Chem. 1956, 21, 394) which condenses with a R1a and Zxe2x80x94H substituted keto-oximes to furnish pyrazoles with high regioselectivity (J. Heterocycl. Chem. 1993, 30, 307). Coupling of the resultant Zxe2x80x94H substituted pyrazoles with fragment Axe2x80x94Bxe2x80x2 is accomplished using standard procedures for Z as a carboxylic, amino or sulfonic moiety. For Z as a carboxylate the coupling is accomplished using Weinreb""s procedure (Tetr. Lett. 1977, 48, 4171) with primary amines of the type H2Nxe2x80x94Axe2x80x94Bxe2x80x2. 1-Amination of the isoquinoline is accomplished via formation of the N-oxide followed by treatment with tosyl chloride and then ethanolamine (U.S. Pat. No. 4,673,676). Alternatively, the amination transformation may be accomplished via treatment of the isoquinoline N-oxides with phosphoryl chloride. Subsequent displacement of the resultant 1-chloro substituent is done with appropriate reagents. Deprotection of groups on fragment Zxe2x80x94Axe2x80x94Bxe2x80x2 gives final product. 
In Scheme 2b is illustrated the preparation of 5-amino substituted 1,6-naphthrydine compounds. Compounds of this type can be prepared from 3-nitro-1,6-naphthrydine (Tetr. 1989, 45, 2693). Reduction to the corresponding amine will allow for transformation to the desired 5-membered nitrogen containing heterocycle with Rf and Zxe2x80x94H substitution. Introduction of a 5-amino moiety may be accomplished through the 5-chloro compound (Chem. Pharm. Bull. 1969, 17, 1045) as previously described in Scheme 2a. Suitable protection of the amino substituent is empoloyed before introduction of fragment Axe2x80x94Bxe2x80x2. Conversion to the final product may be accomplished in an analogous fashion to that described in Scheme 2a 
In Scheme 2c is shown how to prepare isoquinolines, which contain a 1,5-diamine substituent, from 7-aminoisoquinoline by suitable protection of the amine as an amide, directed nitration, and deprotection of the amine a 5-nitro-7-aminoisoquinoline may be obtained. The desired 5-membered nitrogen containing heterocycle with Rf and Zxe2x80x94H substitution may be synthesized as previously shown in Scheme 2a. The addition of fragment Axe2x80x94Bxe2x80x2 and the 1-aminoisoquinoline portion would be accomplished as described earlier. The transformation of Axe2x80x94Bxe2x80x2, Rf, and the 4-nitro substituent to Axe2x80x94B, R1a, and a 4-amino group, respectively, is accomplished by previously outlined methods. 
In Scheme 2d is shown how to prepare isoquinolines which contain 1,4-diamine substitution. From 7-aminoisoquinoline, the desired 5-membered nitrogen containing heterocycle with Rf and Zxe2x80x94H substitution may be synthesized as previously shown in Scheme 2a. Nitration to the isoquinoline 4 position may be accomplished using standard conditions to afford a 4-nitro moiety. The addition of fragment Axe2x80x94Bxe2x80x2 and the 1-aminoisoquinoline portion can be accomplished as described earlier. The transformation of Axe2x80x94Bxe2x80x2, Rf, and the 4-nitro substituent to Axe2x80x94B, R1a, and a 4-amino group, respectively, is accomplished by previously outlined methods. 
Scheme 3 illustrates the preparation of an intermediate for 3-aminobenzisoxazole and 3-aminoindazole. Compounds of this general type can be obtained from a fluorocyanobenzaldehyde prepared from commercially available 2-fluoro-5-methylbenzonitrile by first bis-bromination in a nonprotic solvent in the presence of AIBN or other suitable free radical initiator at a temperature ranging from ambient temperature to the reflux temperature of the selected solvent or under a UV light. The bis-bromo compound may then be converted to an aldehyde using a protic solvent in strong acidic or basic conditions at ambient temperature or higher. The aldehyde or the acid equivalent can then be converted to various C-linked ring M by methods which will be described later. 
Scheme 4 outlines the formation of C-linked aminobenzisoxazoles. The aminobenzisoxazole P1 can be obtained by first treating the oxime of acetone with potassium t-butoxide in an aprotic polar solvent, followed by the addition of the fluorocyanophenylheterocycle H and then treatment with a erotic solvent under strongly acidic conditions (J. Heterocycl. chem. 1989, 26, 1293). Coupling and deprotection as described previously gives 3-aminobenzisoxazoles of Formula I. 
Scheme 5 outlines the formation of the C-linked 3-aminoindazoles of Formula I. Protection of the aldehyde as propylene ketal by standard conditions followed by refluxing with hydrazine in ethanol gives 3-aminoindazole ketal. Protection of the amino group with CBZCl and deprotection of the ketal with HCl/MeOH gives the aldehyde. The aldehyde or the acid equivalent can be converted to various C-linked heterocycles as described later. Coupling and deprotection as described previously gives 3-aminoindazoles of Formula I. 
Scheme 6 illustrates the preparation of aminobenzimidazole aldehyde which can be carried onto the C-linked or N-linked heterocycles by the methods described later in the synthesis section. Cyclization of 3,4-diaminobenzoate to give cbz-protected 2-aminobenzimidazole followed by DIBAL reduction and oxidation gives the desired aldehyde. 
Scheme 7 illustrates the preparation of N-linked aminobenzisoxazoles, aminoindazoles, diaminoquinazolines and aminoquinazolines of Formula I. Compounds of this type can be made from the aniline derivative prepared from commercially available 2-fluoro-5-nitrobenzonitrile using tin(II) chloride or other compatible reducing agents in a protic or an aprotic solvent with or without a miscible co-solvent at from ambient temperature to reflux temperature of the selected solvent.
The N-linked 3-aminobenzisoxazoles and 3-aminoindazoles can be obtained as described previously. The N-linked aminoquinazoline and diaminoquinazoline P1""s can be obtained by condensing the fluorocyano compound with formamidine acetate or guanidine hydrochloride (J. Heterocycl. Chem. 1988, 25, 1173). 
Scheme 8 illustrates the preparation of 1-amino-2-benzopyrazine P1 heterocyclic intermediates leading to compounds of Formula I. Compounds of this general type can be obtained from an aminostilbene prepared from commercially available 2-cyano-4-nitrotoluene by first condensing the nitrotoluene with benzaldehyde or one of its analogs in an alcoholic solvent in the presence of an alkoxide base at a temperature ranging from xe2x88x9210xc2x0 C. to the reflux temperature of the selected solvent. The nitrostilbene may then be reduced to aminostilbene by reaction with tin(II) chloride or another compatible reducing agent in a protic solvent with or without a miscible co-solvent at ambient temperature or higher. The aniline may then be carried on to the N-linked or C-linked heterocycles H by the methods previously described. 
Scheme 8 also further outlines transformation of the N-linked and C-linked (not shown) heterocyclic stilbenes to give 1-aminophthalazines of Formula I. Oxidative cleavage of the stilbene double bond according to the method of Narasimhan et al (Synth. Commun 1985, 15(9), 769) or Sheu et al (J. Am Chem. Soc. 1990, 112, 879) or their equivalent should give an aldehyde. The aldehyde can be treated with hydrazine neat or in a polar or apolar solvent at ambient temperature or up to the reflux temperature of the solvent selected to cause ring closure. Group Zxe2x80x94H can then be coupled with group H2Nxe2x80x94Axe2x80x94B according to the methods outlined in Scheme 2a.
The N-linked and C-linked heterocyclic 2-cyanobenzaldehydes prepared in Scheme 8 can also be used as convenient starting materials for the preparation of N-linked 1,3-diaminoisoquinoline intermediate of Scheme 9 and C-linked (not shown) 1,3-diaminoisoquinoline intermediate of Scheme 9 by appropriate adaptation of the chemistry outlined below. The 2-cyanobenzaldehyde can be reduced to the benzylic alcohol by a hydride reducing agent, preferably sodium borohydride, then treated with a sulfonylchloride, methane sulfonyl chloride as suggested by Scheme 9 or an equivalent, using a trialkylamine base and a dry chlorocarbon solvent with cooling. The mesylate and biscyano intermediates can also be converted to the corresponding 1-aminoisoindole P1 and 1-amino-3,4-dihydroisoqunoline P1 respectively. 
Scheme 10 illustrates another approach to preparing the N-linked and C-linked heterocyclic benzylic alcohols intermediates. These compounds may be obtained from 2-cyano-4-nitro-toluene by photochemical benzylic bromination with N-bromosuccinimide in carbon tetrachloride with a sun lamp and at reflux in the presence of a catalytic amount of a radical initiator such as AIBN or dibenzoylperoxide. The benzylic bromide is then readily displaced with potassium acetate under phase transfer conditions using 18-crown-6 as the phase transfer agent along with water and a non-miscible organic co-solvent with or without heating. The resulting acetate is then hydrolyzed with aqueous acid or by transesterification with anhydrous acid in an alcoholic solvent to give a benzylic alcohol. Dependinq upon the further demands of the chemistry involved in heterocycle formation step(s) the benzylic alcohol may be protected according to the methodology recommended by Greene and Wuts. The nitro group of the resulting product can then be reduced to the aniline according to the methods outlined above for Scheme 8 and then carried on to N-linked and C-linked heterocyclic benzylic alcohols of Scheme 10. It should be recognized that these benzylic alcohols can be readily transformed into the benzylic sulfonate ester intermediates of Scheme 9 or oxidized to the benzaldehyde of Scheme 8 by methods known to the skilled practitioner. 
The compounds of the present invention in which the Dxe2x80x94E residue is isoquinazolin-1-one can be prepared as described in Scheme 11. For compounds which are N-linked to heterocycle M, the reaction of 5-nitroisatoic anhydride with formamide at 150xc2x0 C. affords 7-nitroisoquinazolin-1-one which can be reduced to the corresponding 7-aminoisoquinazolin-1-one by a variety of reducing agents. Diazotization, reduction to the hydrazine and N-heterocycle formation can be carried out to afford the isoquinazolin-1-one N-linked to the appropriate heterocycle. For compounds which are C-linked to heterocycle M, the reaction of 5-bromoanthranilic acid with formamide at 150xc2x0 C. affords the 7-bromoisoquinazolin-1-one. This bromide can be converted into an aldehyde or acetyl group which can be then converted into the appropriate C-linked heterocycle. 
The compounds of the present invention in which the Dxe2x80x94E residue is isoquinolin-1-one can be prepared as described in Scheme 12. For compounds which are N-linked to heterocycle M, oxidation of 7-nitroisoquinoline to its corresponding N-oxide followed by sequential treatment with acetic anhydride and then hydroxide will produce the desired 7-nitroisoquinolin-1-one. This transformation can be carried out with other reagents as well. Reduction of the nitro group and subsequent formation of the N-heterocycle will afford the isoquinolin-1-one N-linked to the appropriate heterocycle. For compounds which are C-linked to heterocycle M, analogous chemistry can be used to prepare desired 7-bromoisoquinolin-1-one, which can then be converted into the appropriate aldehyde or acetyl group for subsequent conversion to the C-linked heterocycle. One method for conversion of the bromide to an acetyl group employs palladium catalysed coupling with (ethoxyvinyl)tributyltin followed by acid hydrolysis of the intermediate vinyl ether residue. 
Compounds wherein Dxe2x80x94E is 3-aminobenzisothiazole are exemplified by synthesis on the pyrazole core as shown in Scheme 13. The 4-fluoro-3-cyano-pyrazole intermediate as described previously can be used. Displacement of the fluoro substituent via nucleophilic aromatic substitution methodology with a thio nucleophile followed by the standard Weinreb coupling methodology should afford the desired coupled thiobenzyl intermediate. The nitrile can be converted to the amidine via standard conditions. Oxidation of the sulfide to the sulfoxide with MCPBA followed by the standard closure adopted by Wright et al for the isothiazolones with trichloroacetic anhydride should afford the desired amino-isothiazolones. 
Compounds in which the M-heterocycle is thiazole can be prepared according to the procedures described in Scheme 14. The appropriate Qxe2x80x94Dxe2x80x94E bromide can be converted into a beta-keto ester in several ways. One preferred method involves transmetallation with an alkyllithium reagent followed by quenching with DMF to afford the corresponding aldehyde. Addition of ethyl diazoacetate in the presence of tin (II) chloride affords the beta-keto ester directly. Other methods are available for this conversion, one of which involves Reformatsky reaction of the aldehyde followed by oxidation to the beta-keto ester. 
A second method for converting the bromide into a beta-keto ester involves palladium catalysed coupling with (ethoxyvinyl)tributyltin followed by acidic hydrolysis to afford the corresponding acetyl derivative. Many methods exist for conversion of the acetyl derivative to the beta-keto ester, one preferred method involves reacting the acetyl derivative with a dialkyl carbonate in the presence of a base such as sodium hydride or lithium diisopropylamide. The beta-keto ester can be converted into the corresponding thiazole derivatives by bromination with NBS followed by cyclization with an appropriate thiourea or thioamide in a solvent such as ethanol or tetrahydrofuran. A one pot method for this conversion involves treating the beta-keto ester with hydroxytosyloxyiodobenzene in acetonitrile, which forms an intermediate alpha-tosyloxy-beta-keto ester, followed by addition of a thiourea or thioamide to effect cyclization to the corresponding thiazole. Manipulation of the ester group of these thiazoles can then afford the compounds containing an appropriate Zxe2x80x94Axe2x80x94B group. Where Z=CONH, standard methods of peptide coupling with an appropriate amine can be employed, such as reaction of the ester with an aluminum reagent derived from the amine. Where Z=COCH2, formation of the acid chloride by standard methods can be followed by addition of an appropriate zinc reagent. The R1a group on the thiazole ring can also be manipulated to provide a variety of different groups. For example, when thiourea is used as the cyclization partner, a 2-aminothiazole is produced. This amino group can be readily diazotized and displaced with the appropriate copper halide to afford 2-halothiazoles. The halogen atom can then be readily displaced by a variety of carbon, nitrogen, oxygen and sulfur nucleophiles to produce a wide variety of alkyl, aryl, heteroatom, and heterocyclic derivatives of R1a.
The tetrazole compounds of this invention where Z is xe2x80x94CONHxe2x80x94 can be prepared as exemplified in Scheme 15. An appropriately substituted amine (Dxe2x80x94ENH2) is acylated with ethyl oxalyl chloride. The resulting amide can be converted to the tetrazole either by the methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768, 1993). The amide can be converted to the iminoyl chloride first and the reacted with NaN3 to form the 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. and Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxytetrazole is then coupled with an appropriate amine (BANH2) by the method described by Weinreb (Tetr. Lett. 1977, 48, 4171-4174). Final deprotection as described before yields the desire product. 
The tetrazole compounds of this invention where Z is xe2x80x94COxe2x80x94 can also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using an appropriately substituted acyl chloride as starting material. The ketone-linker can be reduced to compounds where Z is alkyl.
The tetrazole compounds of this invention where Z is xe2x80x94SO2NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O), SO2xe2x80x94 can be prepared as exemplified in Scheme 16. Appropriately substituted thioisocyanate is reacted with sodium azide to give the 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). The thio-compound can be alkylated (J. Org. Chem. 1978, 43, 1197-1200) and then oxidized to the sulfoxide and sulfone. The thio-compound can also be converted to the sulfonyl chloride and the reacted with an amine to give the desired sulfonamide. The tetrazole compounds of this invention where Z is xe2x80x94Oxe2x80x94 can be prepared via the same method described in Scheme 16 by using appropiately substituted isocyanate as the starting material. 
The tetrazole compounds of this invention where Z is xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94 can be prepared from 5-aminotetrazole, which can be prepared by Smiles Rearrangement as shown in Scheme 17. The thio-compound prepared as described in Scheme 3 is alkylated with 2-chloroacetamide. The resulting compound is then refluxed in ethanolic sodium hydroxide to give the corresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products. 
The N-linked imidazole ring M can be synthesized by the synthetic route shown in Scheme 18. Alkylation of Dxe2x80x94Fxe2x80x94NH2 with 2-bromoethylacetate followed by reaction with Gold""s reagent in the presence of a base, such as NaOMe or LDA, form imidazole ring M. 
Additional imidazole derivatives can be made by the general procedures as described in Scheme 18a. Here, P is a protective group for amino group. E is a substituted group or groups. G is an aromatic ring (six, six-six or five-six ring). R1 and/or R2 is H, a substituted alkyl group, or either V or a precusor of (CH2)nV. V is nitro, amino, thio, hydroxy, sulfone, sulfonic ester, sulfoxide, ester, acid, or halide. n is 0 and 1. U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide. Z, A, and B are the same as those described for formula I. 
A general procedure to make 2,4,5-trisubstituted or 4,5-disubstituted imidazole derivatives is described in Scheme 18b. The starting ester b can be obtained by acylation of N,O-dimethylhydroxyamine with ethyl malonyl chloride. After metalation with a lithium reagent, compound a can react with b to give compound C. Compound C can also be directly made from coupling reaction of a with zinc reagent of ethyl malonyl chloride. Compound C can be brominated with NBS to form compound d, which can react with excess NH3 and R1CO2H to afford compound e. The ester group in e can be transferred to other functionalities, which can be further reacted to give compound f. 
The general procedure to make C-linked imidazole ring M is described in Scheme 19. Aldehyde Dxe2x80x94Exe2x80x94CHO from Scheme 1 can be converted into cyano compound by treatment with hydroxyamine and then dehydration with POCl3. The amidine can be obtained from cyano compound by Pinner reaction, which can be cyclized with alpha-halo ester, ketone or aldehyde to form imidazole ring M. 
Pyrazole ring M of the general Formula I such as those described in Scheme 1 can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo esters. Condensations of this type typically afford a mixture of pyrazole regioisomers which can be effectively separated via silica gel column chromatography (Scheme 20). Hydrolysis of the esters followed by coupling with an appropriate amine can afford the desired amide intermediate. Various substituents on the pyrazole can then be manipulated to afford a variety of benzo, heterocyclic and bicylic compounds. 
The above methodology when applied to diketo derivatives also affords a mixture of pyrazole regioisomers. These can be further manipulated to afford the compounds of Formula I as shown in Scheme 21. 
When ketoimidates are used for condensations with hydrazines the corresponding pyrazole amino esters regioadducts are obtained (Scheme 22). Conversion of these intermediates to the final compounds of formula I can then be accomplished by the protection of the amino functionality with a suitable protecting group commonly known to those in the art or by derivatization (e.g. sulfonamide) then following the general synthetic strategy to prepare the compounds of this invention. 
The pyrazole ester intermediate can be further manipulated to the ketones by the cuprate methodology described by Knochel et al (Scheme 23). Alternatively the ester can be reduced to either the alcohol or aldehyde via methods known to those in the art followed by either a reductive amination with an appropriate amine to an alkyl amine or by converting the alcohol to a leaving group which in turn can be displaced with a number of nucleophiles to provide the intermediates which on further manipulations should afford the compounds of this invention. 
Thio compounds such as those described in Scheme 24 can be easily prepared by the conversion of 5-hydroxy pyrazole to its thiol by treatment with Lawesson""s reagent in refluxing toluene. 
Compounds of this invention wherein the pyrazole ring M is replaced with a 1,2,3-triazole can be prepared as outlined in Scheme 25. 
The compounds of this invention where th,e ring M is 1,2,4-triazole can be easily obtained by the methodology of Huisgen et. al. (Liebigs Ann. Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chloro hydrazone) and an appropriate nitrile dipolarophile as in Scheme 26. 
This methodology provides a wide variety of 1,2,4 triazoles with a varied substitution pattern at the 1,3 and 5 positions. Alternatively the 1,2,4 triazoles can also be prepared by the methodology of Zecchi et al (Synthesis 1986, 9, 772) via an aza Wittig condensation (Scheme 27). 
Alternatively the 1,2,4 triazoles can also be prepared via the methodology of Sauer et al (Tetr. Lett. 1968, 325) by the photolysis of a cyclic carbonate with an appropriate nitile (Scheme 28). 
For compounds of this invention the esters can be converted to the amide intermediates via the Weinreb methodology (i Tetr. Lett. 1977, 48, 4171), i.e., the condensation of an appropriate amine aluminum complex with the ester (Scheme 29). 
Isoxazoline ring M of formula I wherein the 4 and 5 positions are substituted can be prepared following the 1,3-dipolar cycloaddition methodology outlined in Scheme 30. An appropriate benzhydroximinoyl chloride or heterocyclic oximinoylchloride or oxime when subjected to 1,3-dipolar cycloaddition protocol with a suitable 1,2-disubstituted olefin as a dipolarophile should afford a mixture of regioisomers. Separation of the regioisomers by column chromatography followed by the sequence of reactions as described previously should then afford the compounds of choice. Optically active isoxazolines can also be obtained by enzymatic resolution on the regioisomeric esters or by the use of an appropriate chiral auxilliary on the dipolarophile as described by Olsson et al (J. Org. Chem. 1988, 53, 2468). 
In the case of compounds with general formula I wherein Z is an amide the cycloaddition process described in Scheme 30 utilizes an appropriately substituted crotonate ester. The crotonate esters can be obtained from commercial sources or can be obtained from ethyl-4-bromocrotonate by nucleophilic displacement reactions shown in Scheme 31. 
Trisubstituted olefins as dipolarophiles can be obtained from ethylpropiolate by the cuprate chemistry (Scheme 32) according to the method described by Deslongchamps et al (Synlett 1994, 660). 
Compounds of this invention with 1,3,4-triazole ring M can be easily obtained via the methodology of Moderhack et al (J. Prakt. Chem. 1996, 338, 169) as in Scheme 33. 
This reaction involves the condensation of a carbazide with an appropriately substituted commercially available thio-isocyanate to the cyclic thiourea derivative as described previously. Alkylation or nucleophilic displacement reactions on the thiono intermediate then affords a thio alkyl or aryl intermediate which can be hydrolysed, oxidized and decarboxylated to the 5-H-2-thio-triazole intermediate which can be effectively converted to the compounds of this invention. Alternatively the thiono urea intermediate can be oxidized directly to the 2-H-triazole which can then be converted to the ester and then subjected to a variety of reactions shown above to obtain the compounds of this invention. The esters can also be converted to the amine via the Hoffmann rearrangement and this methodology provides a variety of analogs similar to those shown previously. The cyclic thiono urea intermediate can also be oxidized to the sulfonyl chloride by methods shown previously. This in turn can provide the sulfonamides shown in Scheme 34. 
Scheme 35 describes the general synthesis for pyrazoles which have thio and oxidized sulfur derivatives. An appropriately substituted amine is alkylated with ethyl bromoacetate and hydrolyzed to the glycine derivative. Preparation of the N-nitroso compound was easily achieved with sodium nitrite (J. Chem. Soc. 1935, 899). Cyclization to the syndone using acetic anhydride (J. Chem. Soc. 1935, 899) was following by the introduction of the sulfide unit using a sulfoxide as solvent and acetyl chloride as a activating reagent (Tetr. 1974, 30, 409). Photolytic cleavage of the sydnone in the presence of an acetylenic compound the 1,3,5 trisubstituted pyrazole as the major regioisomer (Chem. Ber. 1979, 112, 1206). These can be carried on, as described before, to the final compounds containing the sulfide, sulfoxide or sulfone functionality. 
Scheme 36 shows one possible synthesis of isoxazoles. Substituted benzaldehydes are reacted with hydroxyl amine then chlorinated to give the hydroximinoyl chloride according to the procedure of (J. Org. Chem. 1980, 45, 3916). Preparation of the nitrile oxide in situ with triethylamine and cycloaddition with a substituted alkyne gives a mixture of regioisomeric isoxazoles as shown by H. Kawakami (Chem. Lett. 1987, 1, 85). Preparation of the disubstituted alkyne is achieved by nucleophilic attack of the alkynyl anion on an electrophile as shown by Jungheim et al (J. Org. Chem. 1987, 57, 4007).
Alternatively, one could make the hydroxyiminoyl chloride of the Rla piece and react it with an appropriately substituted alkyne to give another set of regioisomeric isoxazoles which can be separated chromatographically. 
An alternate procedure which produces only one regioisomer is described in Scheme 37. The methylated form of V can be deprotonated and silylated. Chlorination with carbon tetrachloride or fluorination with difluorodibromomethane under triethylborane catalysis give the geminal dihalo compound as shown by Sugimoto (Chem. Lett. 1991, 1319). Cuprate-mediated conjugate addition-elimination give the desired alkene as in Harding (J. Org. Chem. 1978, 43, 3874).
Alternatively, one can acylate with an acid chloride to form a ketone as in Andrews (Tetr. Lett. 1991, 7731) followed by diazomethane to form the enol ether. Each of these compounds can be reacted with a hydroximinoyl chloride in the presence of triethylamine to give one regioisomeric isoxazole as shown by Stevens (Tetr. Lett. 1984, 4587). 
When core substitutent R1a is CH2xe2x80x94R1xe2x80x2, the synthesis is shown in Scheme 38. After being treated with LDA, the ketone starting material reacts with PhSSO2Ph to give the phenylthiolated compound which reacts with hydrazine in acetic acid to form pyrazole derivative. The pyrazole ester reacts with an amine or aniline (previously treated with AlMe3) to provide amide. Oxidation of the sulfide with mCPBA gives the corresponding sulfone. Deprotonation of the sulfone with base, followed by trapping with an electrophile(Exe2x80x94X) and treatment with SmI2 provided the desired compound after deprotection. 
Scheme 39 shows other methods of synthesis for R1axe2x95x90CH2R1xe2x80x2 or COR1xe2x80x2. Protection of the hydroxyl group of hydroxyacetone with a benzyl halide and treatment with a base and CO(CO2Et)2 gives the tricarbonyl compound. Refluxing with NH2OMe.HCl in pyridine and ethanol in the presence of molecular sieve 3 xc3x85 gives the oxime. Cyclization of oxime with Dxe2x80x94Exe2x80x94NHNH2 provided pyrazole, which can be converted into the corresponding amide by reacting with an amine or aniline (previously activated with AlMe3). Debenzylation by catalytic hydrogenation provides the alcohol. The alcohol is converted into the tosylate with TsCl, followed by replacement with a nucleophile to provide the desired compound. The alcohol can also be oxidized to the corresponding aldehyde or acid, or further converted to ester or amide. 
Scheme 40 shows the synthesis of pyrazole ring with a chloride group. Chlorination of pyrazole starting material obtained previously in Scheme 2a with NCS formed chloropyrazole. The chloropyrazole can be reacted with an aniline in the presence of AlMe3 followed by amination as described in Scheme 2a to give the desired product. 
Scheme 41 describes the synthesis of compounds wherein M is a benzene ring and V is a nitro, protected sulfonamide or ester group and precursor of group Z of Formula I. The V group is placed on an appropriately substituted phenol either via nitration as shown by Poirier et al. (Tetrahedron 1989, 45(5), 1415), sulfonylation as shown by Kuznetsov (Akad. Nauk SSSR Ser. Khim 1990, 8, 1888) or carboxylation by Sartori et al. (Synthesis 1988, 10, 763). Bromination with triphenylphosphine and bromine (J. Am. Chem. Soc. 1964, 86, 964) gives the desired bromide. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine. 
Schemes 42-45 describe the synthesis of compounds wherein M is pyridine. Each scheme represents a different substitution pattern for the pyridine ring. In Scheme 42, a suitably protected aldehyde is subjected to base-catalyzed condensation with an activated ester to give after deprotection the desired aldehyde. Refluxing with ammonium chloride as shown by Dornow and Ische (Chem. Ber. 1956, 89, 876) provides the pyridinol which is brominated with POBr, (Tjeenk et al. Rec. Trav. Chim. 1948, 67, 380) to give the desired 2-bromopyridine. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine. 
Treatment of an appropriately substituted 5-ethoxyoxazole with an alkene as shown by Kondrat""eva et al. (Dokl. Akad. Nauk SSSR 1965, 164, 816) provides a pyridine with the V substituent at the para position. Bromination at the 3-position as shown by van der Does and Hertog (Rec. Trav. Khim. Pays-Bas 1965, 84, 951) followed by palladium-catalyzed boronic acid coupling provides the desired substituted pyridine. 
Scheme 44 describes a synthesis of a third substitution pattern on a pyridine ring. The appropriate tricarbonyl compound which can be prepared by methods described in Scheme 42 is treated with ammonium chloride to form the pyridinol which is subsequently brominated. Palladium-catalyzed coupling provides the desired substituted pyridine. 
Scheme 45 takes a suitably substituted dicarbonyl compound and by chemistry illustrated in Schemes 42 and 44, reacts it with ammonium chloride. Bromination gives the 3-bromopyridine which upon palladium-catalyzed coupling provides the desired substituted pyridine. 
Schemes 46-48 describe the synthesis of compounds wherein M is pyridazine. Each scheme represents a different substitution pattern for the pyridine ring. In Scheme 46 an activated ester is reacted with an appropriately substituted xcex1-keto aldehyde and hydrazine as shown by Schmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467). Conversion of the pyridazinone to the bromide using POBr3 and palladium-catalyzed coupling provides the desired substituted pyridazine. 
In Scheme 47, glyoxal can react under basic conditions with an activated ketone and subsequently brominated/dehydrobrominated to give the desired ketoaldehyde. Alternatively, a protected ketone can react with an activated aldehyde, undergo bromination/dehydrobromination, be deprotected and oxidized to give the regioisomeric ketoaldehyde. Cyclization as shown by Sprio and Madonia (Ann. Chim. 1958, 48, 1316) with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine. 
By analogy to Scheme 47, in Scheme 48, a aldehyde can be reacted with an activated ketone, brominated, dehydrobrominated and deprotected to give the desired diketone. Alternatively, a regioisomeric ketone can be placed through the same reaction sequence to produce an isomeric keto aldehyde. Reaction with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine. 
Schemes 49 and 50 describe the synthesis of compounds wherein M is pyrimidine. Each scheme represents a different substitution pattern for the pyrimidine ring. In Scheme 49, a condensation with an appropriately substituted acid chloride and an activated ester followed by conjugate reduction by tin hydride (Moriya et al. J. Org. Chem. 1986, 51, 4708) gives the desired 1,4 dicarbonyl compound. Cyclization with formamidine or a substituted amidine followed by bromination gives the desired regioisomeric pyrimidine. Palladium-catalyzed coupling provides the desired substituted pyrimidine. 
Using similar chemistry, Scheme 50 shows how an amidine can be condensed with a 1,3-dicarbonyl compound and subsequently brominated in the 5-position (J. Het. Chem. 1973, 10, 153) to give a specific regioisomeric bromopyrimidine. Palladium-catalyzed coupling provides the desired substituted pyrimidine. 
Using the same ketoaldehyde from Scheme 50, cyclization with an appropriately substituted 1,2-diamine (Chimia 1967, 21, 510) followed by aromatization (Helv. Chim. Acta 1967, 50, 1754; provides a regioisomeric mixture of pyrazines as illustrated in Scheme 51. Bromination of the hydrobromide salt (U.S. Pat. No. 2,403,710) yields the intermediate for the palladium-catalyzed coupling step which occurs as shown above. 
Schemes 52 and 53 describe the synthesis of compounds wherein M is a 1,2,3-triazine. In Scheme 52, a vinyl bromide is palladium coupled to a molecule containing the substituent R1b. Allylic bromination followed by azide displacement provide the cyclization precursor. Triphenylphosphine-mediated cyclization (J. Org. Chem. 1990, 55, 4724) give the 1-aminopyrazole which is subsequently brominated with N-bromosuccimide. Lead tetraacetate mediated rearrangement as shown by Neunhoeffer et al. (Ann. 1985, 1732) provides the desired regioisomeric 1,2,3-triazine. Palladium-catalyzed coupling provides the substituted triazine. 
In Scheme 53, an alkene is allylically brominated and the bromide is displaced to give a regioisomer of the azide in Scheme 52. Following the same reaction sequence as shown above, cyclization provides the 1-aminopyrazole. Bromination followed by lead tetraacetate mediated rearrangement give the 1,2,3-triazine. Palladium-catalyzed coupling provides the other desired triazine. 
Schemes 54 and 55 describe the synthesis of compounds wherein M is a 1,2,4-triazine. In Scheme 54, a nitrile is converted using hydrazine to give the amidrazone which is condensed with a xcex1-ketoester to give the triazinone as shown by Paudler and Lee (J. Org. Chem. 1971, 36, 3921). Bromination as shown by Rykowski and van der Plas (J. Org. Chem. 1987, 52, 71) followed by palladium-catalyzed coupling provides the desired 1,2,4-triazine. 
In Scheme 55, to achieve the opposite regioisomer the reaction scheme shown above is modify by the substituting a protect xcex1-ketoester. This allows the most nucleophilic nitrogen to attack the ester functionality setting up the opposite regiochemistry. Deprotection and thermal cyclization gives the triazinone which is brominated as shown above.
Palladium-catalyzed coupling provides the other desired 1,2,4-triazine. 
Scheme 56 describes the synthesis of compounds wherein M is a 1,2,3,4-tetrazine. Lithiation of a vinyl bromide, transmetallation with tin, palladium catalyzed carbonylation and hydrazone formation provides a diene for a subsequent Diels-Alder reaction as shown by Carboni and Lindsey (J. Am. Chem. Soc. 1959, 81, 4342). Reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate should give after bromination the desired 1,2,3,4-tetrazine. Palladium-catalyzed coupling provides the desired substitution. 
Compounds of this invention where B is either a carbocyclic or heterocyclic residue as defined in Formula I are coupled to A as shown generically and by specific example in Scheme 57, either or both of A and B may be substituted with 0-2 R4. W is defined as a suitable protected nitrogen, such as NO2 or NHBOC; a protected sulfur, such as S-tBu or SMOM; or a methyl ester. Halogen-metal exchange of the bromine in bromo-B with n-butyl lithium, quenching with triisopropyl borate and acidic hydrolysis should give the required boronic acid, Bxe2x80x2xe2x80x94B(OH)2. The Wxe2x80x94Axe2x80x94Br subunit may be already linked to ring M before the Susuki coupling reaction. Deprotection can provide the complete subunit. 
Scheme 58 describes a typical example of how the Axe2x80x94B subunit can be prepared for attachment to ring M. 4-Bromoaniline can be protected as Boc-derivative and the coupled to 2-(t-butylamino)sulfonylphenylboronic acid under Suzuki conditions. 2-(t-Butylamino)sulfonylphenylboronic acid can be prepared by the method described by Rivero (Bioorg. Med. Chem. Lett. 1994, 189). Deprotection with TFA can provide the aminobiphenyl compound. The aminobiphenyl can then be coupled to the core ring structures as described below. 
For N-substituted heterocycles, Scheme 59 shows how the boronic acid can be formed by a standard literature procedure (Ishiyama, T.; Murata, M.; and Miyaura, N. J. Org. Chem. 1995, 60, 7508-7510). Copper-promoted Cxe2x80x94N bond coupling of the boronic acid and heterocycle can be performed as described (Lam, P. Y. S.; et. al., Tet. Lett. 1998, 39, 2941-2944). It is preferrable to use boroxine or unhindered borate as the boron source. The acid obtained can be condensed with Hxe2x80x94Axe2x80x94Bxe2x80x2 and after deprotection yields the desired product. 
A synthetic route for making aminobenzisoxazole derivatives with an imidazole core is shown in Scheme 60. Palladium(0)-catalyzed cross-coupling reaction of an alkoxydiboron (pinacol diborate) with a haloarene (see, Ishiyama et al, J. Org. Chem. 1995, 60, 7508-7510) should afford an arylborate intermediate, which can be hydrolyzed with 4M HCl (10 eq.) in a minimum amount of THF at room temperature to give arylboronic acid. 4-Imidazolecarboxylic acid can be converted to 4-trifluoromethylimidazole by reacting with SF4 (3 eq.) and HF (7.5 eq.) in a shaker tube at 40xc2x0 C. Copper(II)-catalyzed coupling reaction of arylboronic acid with 4-trifluoromethylimidazole in the presence of pyridine (5 eq.) and 4 xc3x85 molecular sieves in THF should provide 1-aryl-4-trifluoromethylimidazole. Lithiation of the imidazole with n-BuLi, followed by quenching with methylchloroformate, can give 1-aryl-4-trifluoromethyl-1H-imidazole-5-methylcarboxylate. Nucleophilic replacement of fluorobenzene with pre-mixed potassium tert-butoxide and acetone oxime followed by treatment with 20% HCl in ethanol can form 1-aminobenzisoxazole-4-trifluoromethyl-1H-imidazole-5-methylcarboxylate. The ester may then be converted to an amide by a Weinreb coupling reaction. Alternatively, after the saponification of the ester in aqueous NaOH in THF, the resulting acid can be converted to the corresponding acyl chloride upon treatment with SOCl2 or oxalyl chloride, followed by reacting with aniline containing an o-substituent to form an amide. Fluorobenzene can similarly be converted to aminobenzisoxazole derivative by treatment with pre-mixed potassium tert-butoxide and acetone oxime, followed by reaction with 20% HCl in ethanol. The ester can also be saponified in aqueous NaOH in THF to give an acid, which then can be coupled with aniline to give amide via a coupling reagent (ex. PyBrop) under basic conditions. 
o-Fluorobenzonitrile derivatives with imidazole core can be converted to 1-aminoquinazoline-1H-imidazole derivatives by treatment with formamidine salt in pyridine and ethanol (Scheme 61). 
Scheme 62 illustrates the preparation of bicyclic core intermediates leading to compounds with indazole and indole cores. Compounds of the general type can be obtained by the method outlined in Chem. Ber. (1926) 35-359. The pyrazole N-oxide can be reduced by any number of methods including triphenylphosphine in refluxing toluene followed by the hydrolysis of the nitrile substituent to a carboxylic acid with basic hydrogen peroxide to give indazole intermediate which may be coupled in the usual way to give indazole product. Indole intermediate may be obtained via the Fischer Indole Synthesis (Org. Syn, Col. Vol. III 725) from an appropriately substituted phenylhydrazine and acetophenone. Further elaboration using standard synthetic methods including the introduction of a 3-formyl group by treatment with POCl3 in DMF, the optional protection of the indole NH with the Sem group (TMSCH2CH2OCH2Cl, NaH, DMF) and oxidation of the aldehyde to a carboxylic acid which is now ready for transformation to indole product. 
When B is defined as Xxe2x80x94Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practitioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practitioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.
The chemistry of Table A can be carried out in aprotic vents such as a chlorocarbon, pyridine, benzene or toluene, temperatures ranging from xe2x88x9220xc2x0 C. to the reflux point of the vent and with or without a trialkylamine base.
The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0xc2x0 C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (xe2x88x9220xc2x0 C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide-dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)3 according to Fiandanese et al. (Tetr. Lett. 1984, 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetr. Lett. 1992, 33(31), 4437).
The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.